Neoplastic diseases, also referred to as cancers, are a leading cause of illness and death throughout the world. Neoplastic diseases can be grouped into different classes, based on the types of cells involved. Solid tumors can originate from numerous cells types and generally form masses in a patient. In contrast, non-solid tumors, such as hematological malignancies, generally originate from cells of the blood, bone marrow or lymphatic system.
Some current therapies for hematological malignancies, e.g., various types of leukemia, are able to achieve a high rate of remission. Therapy to induce remissions typically involves dosing with regimens of cytotoxic agents (e.g., low or high dose cytarabine and daunomycin) and/or targeted delivery of cytotoxic agents (e.g., Mylotarg®, gemtuzamab ozogamicin, Wyeth). Such treatments are able to induce remissions. For example, treatment of patients with acute myeloid leukemia (AML) an induction regimen of cytarabine and anthracycline can induce remissions in most younger patients (i.e., less than 60 years of age). Consolidation regimens that include high-dose cytarabine, autologous or allogenic transplantation can extend remission intervals in younger patients with AML and can cure approximately one third of such patients who achieve remissions. Many patients, however, and in particular elderly patients, are untreatable with such agents because they cannot tolerant high doses of chemotherapeutic agents. In addition, a large percentage of such patients who achieve remission ultimately relapse. While a large body of work has addressed the early detection of relapse and of minimal residual disease, effective strategies for treating patients in remission to prevent or delay relapse or recurrence of the underlying hematological malignancy are lacking.
Although controversial, it has been suggested that non-malignant effector or accessory cells (e.g., monocytes and macrophages) may contribute to cancer growth and metastasis through the secretion of inflammatory mediators and growth factors, and the production of proteases. Tumor growth and progression have been linked to inflammation and the presence of tumor-associated macrophages (TAMs) (see, e.g., Colombo and Mantovani, 2005, Cancer Res. 65:9113-9116). Monocytes and macrophages form a major component of the inflammatory infiltrate associated with many carcinomas. Monocytes differentiate into macrophages (i.e., TAMs) in the cytokine- and chemokine-rich environments provided by the infiltrating cells and the tumor cells. TAMs secrete numerous pro-inflammatory cytokines and chemokines that enhance and promote the growth and metastases of tumors. High numbers of TAMs in cancer tissues have been linked to poor prognosis and patient survival in many cancers, including those of the breast, prostate, bladder, kidney, and esophagus (see, e.g., Lewis and Pollard, 2006, Cancer Res. 66:605-612).
Non-malignant monocytes and macrophages, including TAMs, may also play a role in cancer-associated cachexia. Patients with neoplastic disease often experience related cancer-associated challenges. Cancer-associated cachexia (also referred to as cancer cachexia) is a condition that occurs at high frequency in cancer patients and involves wasting, fever, night sweats and weight loss, often accompanied by anorexia. Cancer-associated cachexia is a major cause of morbidity and mortality in advanced cancer patients, in particular with cancers of the breast, prostate, lung, pancreas, and gastrointestinal tract. The cause of cancer-associated cachexia is still unknown; however, this condition is associated with a chronic, systemic inflammatory response and the elevation of acute phase proteins (see, e.g., Esper and Harb, 2005, Nutr. Clin. Pract. 20:369-376; Tisdale, 2001, Nutrition 17:438-442; Gordon et al., 2005, Q. J. Med. 98:779-788).
Inflammatory mediators, cytokines, chemokines and growth factors produced by non-malignant effector cells, alone or in concert with the tumor cells, include, but are not limited to, tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ), leukemia inhibitory factor (LIF), IP-10 and proteolysis-inducing factor (PIF). These inflammatory mediators, cytokines, chemokines and growth factors may play a role in cancer growth and progression, and are thought to contribute to the persistent inflammatory condition associated with cachexia.
A variety of pharmacological agents have been administered to patients with cancer-associated cachexia and/or tested in animal models. These treatments have been met, however, with only limited success (see, e.g., Illman et al., 2005, J. Support. Oncol. 3:37-50; Gordon et al., 2005, Q. J. Med. 98:779-788).
Just as in cancer, monocytes and macrophages are a major source of cytokines and chemokines believed to contribute to the pathology of acute and chronic autoimmune or inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, peritonitis, psoriasis, atopic dermatitis, psoriatic arthritis, and multiple sclerosis). These cells are involved in the recruitment, differentiation and maturation of more macrophages to the inflamed regions and in the release and activation of proteases that destroy tissues (see, e.g., Ma and Pope, 2005, Curr. Pharm. Design 11: 569-580; Bruck et al., 1996, Immunobiology 195:588-600; Liu and Pope, 2004, Rheum. Dis. Clin. N. Am. 30:19-39).
While there are no known cures for autoimmune and inflammatory diseases (e.g., rheumatoid arthritis, psoriasis), therapies are available to reduce inflammation and pain and tissue destruction. These therapies are not effective, however, in all patients and are associated with many side-effects.
New therapies are needed, therefore, for treating cancer, cancer-associated cachexia and autoimmune and inflammatory diseases to improve the quality of life and survival rates for patients with cancer or an autoimmune or inflammatory disease.